Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 352
Filtrar
1.
Molecules ; 29(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474691

RESUMO

Inhibition of glycoside hydrolases has widespread application in the treatment of diabetes. Based on our previous findings, a series of dihydrofuro[3,2-b]piperidine derivatives was designed and synthesized from D- and L-arabinose. Compounds 32 (IC50 = 0.07 µM) and 28 (IC50 = 0.5 µM) showed significantly stronger inhibitory potency against α-glucosidase than positive control acarbose. The study of the structure-activity relationship of these compounds provides a new clue for the development of new α-glucosidase inhibitors.


Assuntos
Acarbose , Inibidores de Glicosídeo Hidrolases , Inibidores de Glicosídeo Hidrolases/farmacologia , Relação Estrutura-Atividade , Acarbose/farmacologia , alfa-Glucosidases/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular
2.
Int J Biol Macromol ; 263(Pt 1): 130175, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38360242

RESUMO

Diabetes mellitus is a multifactorial disease and its effective therapy often demands several drugs with different modes of action. Herein, we report a rational design and synthesis of multi-targeting novel molecular hybrids comprised of EGCG and quinoxaline derivatives that can effectively inhibit α-glucosidase, α-amylase as well as control oxidative stress by scavenging ROS. The hybrids showed superior inhibition of α-glucosidase along with similar α-amylase inhibition as compared to standard drug, acarbose. Most potent compound, 15c showed an IC50 of 0.50 µM (IC50 of acarbose 190 µM) against α-glucosidase. Kinetics studies with 15c revealed a competitive inhibition against α-glucosidase. Binding affinity of 15c (-9.5 kcal/mol) towards α-glucosidase was significantly higher than acarbose (-7.7 kcal/mol). 15c exhibited remarkably high antioxidant activity (IC50 = 18.84 µM), much better than vitamin C (IC50 = 33.04 µM). Of note, acarbose shows no antioxidant activity. Furthermore, α-amylase activity was effectively inhibited by 15c with an IC50 value of 16.35 µM. No cytotoxicity was observed for 15c (up to 40 µM) in MCF-7 cells. Taken together, we report a series of multi-targeting molecular hybrids capable of inhibiting carbohydrate hydrolysing enzymes as well as reducing oxidative stress, thus representing an advancement towards effective and novel therapeutic approaches for diabetes.


Assuntos
Diabetes Mellitus , Hipoglicemiantes , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Acarbose/farmacologia , Acarbose/química , alfa-Glucosidases/metabolismo , alfa-Amilases/química , Quinoxalinas/farmacologia , Antioxidantes/química , Estresse Oxidativo , Simulação de Acoplamento Molecular , Inibidores de Glicosídeo Hidrolases/química
3.
Food Funct ; 15(4): 2234-2248, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38318730

RESUMO

A promising and efficacious approach to manage diabetes is inhibiting α-glucosidase and α-amylase activity. Therefore, the inhibitory activities of five natural sweeteners (mogrosides (Mog), stevioside (Ste), glycyrrhizinic acid (GA), crude trilobatin (CT), and crude rubusoside (CR)) against α-glucosidase and α-amylase and their interactions were evaluated in vitro using enzyme kinetics, fluorescence spectroscopy, Fourier infrared spectroscopy, and molecular docking. The inhibitor sequence was CT > GA > Ste, as GA competitively inhibited α-glycosidase activity while CT and Ste exhibited mixed inhibitory effects. Compared to a positive control acarbose, the inhibitory activity of CT was higher. For α-amylase, the mixed inhibitors CT, CR, and Mog and the competitive inhibitor Ste effectively inhibited the enzyme, with the following order: CT > CR > Ste > Mog; nevertheless, the inhibitors were slightly inferior to acarbose. Three-dimensional fluorescence spectra depicted that GA, CT, and CR bound to the hydrophobic cavity of α-glucosidase or α-amylase and changed the polarity of the hydrophobic amino acid-based microenvironment and structure of the polypeptide chain backbone. Infrared spectroscopy revealed that GA, CT, and CR could disrupt the secondary structure of α-glucosidase or α-amylase, which decreased enzyme activity. GA, trilobatin and rubusoside bound to amino acid residues through hydrogen bonds and hydrophobic interactions, changing the conformation of enzyme molecules to decrease the enzymatic activity. Thus, CT, CR and GA exhibit promising inhibitory effects against α-glucosidase and α-amylase.


Assuntos
Acarbose , Diterpenos do Tipo Caurano , Flavonoides , Glucosídeos , Inibidores de Glicosídeo Hidrolases , Polifenóis , Acarbose/farmacologia , Acarbose/química , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , alfa-Amilases/metabolismo , Estrutura Secundária de Proteína , Aminoácidos
4.
BMC Complement Med Ther ; 24(1): 65, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291462

RESUMO

BACKGROUND: Type 2 Diabetes mellitus (DM) is an affliction impacting the quality of life of millions of people worldwide. An approach used in the management of Type 2 DM involves the use of the carbohydrate-hydrolyzing enzyme inhibitor, acarbose. Although acarbose has long been the go-to drug in this key approach, it has become apparent that its side effects negatively impact patient adherence and subsequently, therapeutic outcomes. Similar to acarbose in its mechanism of action, bee propolis, a unique natural adhesive biomass consisting of biologically active metabolites, has been found to have antidiabetic potential through its inhibition of α-amylase. To minimize the need for ultimately novel agents while simultaneously aiming to decrease the side effects of acarbose and enhance its efficacy, combination drug therapy has become a promising pharmacotherapeutic strategy and a focal point of this study. METHODS: Computer-aided molecular docking and molecular dynamics (MD) simulations accompanied by in vitro testing were used to mine novel, pharmacologically active chemical entities from Egyptian propolis to combat Type 2 DM. Glide docking was utilized for a structure-based virtual screening of the largest in-house library of Egyptian propolis metabolites gathered from literature, in addition to GC-MS analysis of the propolis sample under investigation. Thereafter, combination analysis by means of fixed-ratio combinations of acarbose with propolis and the top chosen propolis-derived phytoligand was implemented. RESULTS: Aucubin, identified for the first time in propolis worldwide and kaempferol were the most promising virtual hits. Subsequent in vitro α-amylase inhibitory assay demonstrated the ability of these hits to significantly inhibit the enzyme in a dose-dependent manner with an IC50 of 2.37 ± 0.02 mM and 4.84 ± 0.14 mM, respectively. The binary combination of acarbose with each of propolis and kaempferol displayed maximal synergy at lower effect levels. Molecular docking and MD simulations revealed a cooperative binding mode between kaempferol and acarbose within the active site. CONCLUSION: The suggested strategy seems imperative to ensure a steady supply of new therapeutic entities sourced from Egyptian propolis to regress the development of DM. Further pharmacological in vivo investigations are required to confirm the potent antidiabetic potential of the studied combination.


Assuntos
Diabetes Mellitus Tipo 2 , Própole , Humanos , Acarbose/farmacologia , Acarbose/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Quempferóis , Própole/farmacologia , Simulação de Acoplamento Molecular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Egito , Qualidade de Vida , alfa-Glucosidases/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , alfa-Amilases/metabolismo
5.
Bioorg Chem ; 144: 107106, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38244380

RESUMO

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood sugar levels. It was shown that modulating the activity of α-glucosidase, an enzyme involved in carbohydrate digestion and absorption, can improve blood sugar control and overall metabolic health in individuals with T2DM. As a result, in the current study, a series of imidazole bearing different substituted thioquinolines were designed and synthesized as α-glucosidase inhibitors. All derivatives exhibited significantly better potency (IC50 = 12.1 ± 0.2 to 102.1 ± 4.9 µM) compared to the standard drug acarbose (IC50 = 750.0 ± 5.0 µM). 8g as the most potent analog, indicating a competitive inhibition with Ki = 9.66 µM. Also, the most potent derivative was subjected to molecular docking and molecular dynamic simulation against α-glucosidase to determine its mode of action in the enzyme and study the complex's behavior over time. In vivo studies showed that 8g did not cause acute toxicity at 2000 mg/kg doses. Additionally, in a diabetic rat model, treatment with 8g significantly reduced fasting blood glucose levels and decreased blood glucose levels following sucrose loading compared to acarbose, a standard drug used for blood sugar control. The findings suggest that the synthesized compound 8g holds promise as an α-glucosidase inhibitor for improving blood sugar control and metabolic health.


Assuntos
Diabetes Mellitus Tipo 2 , Nitroimidazóis , Ratos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , alfa-Glucosidases/metabolismo , Acarbose/farmacologia , Acarbose/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Simulação de Acoplamento Molecular , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Nitroimidazóis/uso terapêutico , Relação Estrutura-Atividade , Estrutura Molecular
6.
Inflammopharmacology ; 32(1): 355-376, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38170330

RESUMO

BACKGROUND: Although a large number of trials have observed an anti-inflammatory property of acarbose, the currently available research remains controversial regarding its beneficial health effects. Hence, the purpose of this study was to examine the effect of acarbose on inflammatory cytokines and adipokines in adults. METHODS: PubMed, Web of Science, and Scopus were systematically searched until April 2023 using relevant keywords. The mean difference (MD) of any effect was calculated using a random-effects model. Weighted mean difference (WMD) and 95% confidence intervals (CIs) were calculated via the random-effects model. RESULTS: The current meta-analysis of data comprised a total of 19 RCTs. Meta-analysis showed that acarbose significantly decreased tumor necrosis factor-alpha (TNF-α) (weighted mean difference [WMD]) = - 4.16 pg/ml, 95% confidence interval (CI) - 6.58, - 1.74; P = 0.001) while increasing adiponectin (WMD = 0.79 ng/ml, 95% CI 0.02, 1.55; P = 0.044). However, the effects of acarbose on TNF-α concentrations were observed in studies with intervention doses ≥ 300 mg/d (WMD = - 4.09; 95% CI - 7.00, - 1.18; P = 0.006), and the adiponectin concentrations were significantly higher (WMD = 1.03 ng/ml, 95%CI 0.19, 1.87; P = 0.016) in studies in which the duration of intervention was less than 24 weeks. No significant effect was seen for C-reactive protein (CRP; P = 0.134), interleukin-6 (IL-6; P = 0.204), and leptin (P = 0.576). CONCLUSION: Acarbose had beneficial effects on reducing inflammation and increasing adiponectin. In this way, it may prevent the development of chronic diseases related to inflammation. However, more studies are needed.


Assuntos
Adipocinas , Citocinas , Adulto , Humanos , Acarbose/farmacologia , Acarbose/uso terapêutico , Adiponectina , Fator de Necrose Tumoral alfa , Ensaios Clínicos Controlados Aleatórios como Assunto , Interleucina-6 , Inflamação/tratamento farmacológico
7.
J Biomol Struct Dyn ; 42(1): 314-325, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-36995074

RESUMO

Due to its clinical and cosmetic applications, investigators have paid attention to tyrosinase (TYR) inhibitor development. In this study, a TYR inhibition study with acarbose was investigated to gain insights into the regulation of the catalytic function. Biochemical assay results indicated that acarbose was turned to be an inhibitor of TYR in a reversible binding manner and probed as a distinctive mixed-type inhibitor via measurement of double-reciprocal kinetic (Ki = 18.70 ± 4.12 mM). Time-interval kinetic measurement indicated that TYR catalytic function was gradually inactivated by acarbose in a time-dependent behavior displaying with a monophase process that was evaluated by semi-logarithmic plotting. Spectrofluorimetric measurement by integrating with a hydrophobic residue detector (1-anilinonaphthalene-8-sulfonate) showed that the high dose of acarbose derived a conspicuous local structural deformation of the TYR catalytic site pocket. Computational docking simulation showed that acarbose bound to key residues such as HIS61, TYR65, ASN81, HIS244, and HIS259. Our study extends an understanding of the functional application of acarbose and proposes that acarbose is an alternative candidate drug for a whitening agent via direct retardation of TYR catalytic function and it would be applicable for the relevant skin hyperpigmentation disorders concerning the dermatologic clinical purpose.Communicated by Ramaswamy H. Sarma.


Assuntos
Simulação de Dinâmica Molecular , Monofenol Mono-Oxigenase , Monofenol Mono-Oxigenase/metabolismo , Acarbose/farmacologia , Inibidores Enzimáticos/química , Domínio Catalítico , Simulação de Acoplamento Molecular , Cinética
8.
Molecules ; 28(23)2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-38067659

RESUMO

A new indole diterpene, 26-dihydroxyaflavininyl acetate (1), along with five known analogs (2-6) were isolated from the liquid fermentation of Aspergillus flavus GZWMJZ-288, an endophyte from Garcinia multiflora. The structures of these compounds were identified through NMR, MS, chemical reaction, and X-ray diffraction experiments. Enzyme inhibition activity screening found that compounds 1, 4, and 6 have a good binding affinity with NPC1L1, among which compound 6 exhibited a stronger binding ability than ezetimibe at a concentration of 10 µM. Moreover, compound 5 showed inhibitory activity against α-glucosidase with an IC50 value of 29.22 ± 0.83 µM, which is 13 times stronger than that of acarbose. The results suggest that these aflavinine analogs may serve as lead compounds for the development of drugs targeting NPC1L1 and α-glucosidase. The binding modes of the bioactive compounds with NPC1L1 and α-glucosidase were also performed through in silico docking studies.


Assuntos
Aspergillus flavus , Garcinia , Aspergillus flavus/metabolismo , alfa-Glucosidases/metabolismo , Acarbose/farmacologia , Difração de Raios X , Inibidores de Glicosídeo Hidrolases/química , Estrutura Molecular , Simulação de Acoplamento Molecular
9.
Respir Res ; 24(1): 312, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38098038

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) is widely prevalent worldwide, and respiratory tract infections (RTIs) have become the primary cause of death for T2DM patients who develop concurrent infections. Among these, Pseudomonas aeruginosa infection has been found to exhibit a high mortality rate and poor prognosis and is frequently observed in bacterial infections that are concurrent with COVID-19. Studies have suggested that acarbose can be used to treat T2DM and reduce inflammation. Our objective was to explore the effect of acarbose on P. aeruginosa RTI in T2DM individuals and elucidate its underlying mechanism. METHODS: High-fat diet (HFD) induction and P. aeruginosa inhalation were used to establish a RTI model in T2DM mice. The effect and mechanism of acarbose administered by gavage on P. aeruginosa RTI were investigated in T2DM and nondiabetic mice using survival curves, pathological examination, and transcriptomics. RESULTS: We found that P. aeruginosa RTI was more severe in T2DM mice than in nondiabetic individuals, which could be attributed to the activation of the NF-κB and TREM-1 signaling pathways. When acarbose alleviated P. aeruginosa RTI in T2DM mice, both HIF-1α and NF-κB signaling pathways were inhibited. Furthermore, inhibition of the calcium ion signaling pathway and NF-κB signaling pathway contributed to the attenuation of P. aeruginosa RTI by acarbose in nondiabetic mice. CONCLUSIONS: This study confirmed the attenuating effect of acarbose on P. aeruginosa RTIs in T2DM and nondiabetic mice and investigated its mechanism, providing novel support for its clinical application in related diseases.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Infecções por Pseudomonas , Infecções Respiratórias , Humanos , Camundongos , Animais , Acarbose/farmacologia , Acarbose/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Pseudomonas aeruginosa/metabolismo , NF-kappa B/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico
10.
BMC Pharmacol Toxicol ; 24(1): 65, 2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-37990256

RESUMO

PURPOSE: Dyslipidemia, characterized by elevated levels of triglycerides (TG), low-density lipoprotein (LDL), total cholesterol (TC), and reduced levels of high-density lipoprotein (HDL), is a major risk factor for cardiovascular diseases (CVD). Several studies have shown the potential of acarbose in improving serum lipid markers. However, there have been conflicting results on the topic in adults. Therefore, a comprehensive systematic review and meta-analysis was conducted to assess the impact of acarbose on lipid profiles. METHODS: The random-effects approach was used to combine the data, and the results were provided as weighted mean difference (WMD) with 95% confidence intervals (CI). RESULTS: Our meta-analysis included a total of 74 studies with a combined sample size of 7046 participants. The results of the analysis showed that acarbose resulted in a reduction in levels of TG (WMD = - 13.43 mg/dl, 95% CI: - 19.20, - 7.67; P < 0.001) and TC (WMD = - 1.93 mg/dl, 95% CI: - 3.71, - 0.15; P = 0.033), but did not affect other lipid markers. When conducting a nonlinear dose-response analysis, we found that acarbose was associated with an increase in levels of HDL (coefficients = 0.50, P = 0.012), with the highest increase observed at a dosage of 400 mg/d. Furthermore, our findings suggested a non-linear relationship between the duration of the intervention and TC (coefficients = - 18.00, P = 0.032), with a decline observed after 50 weeks of treatment. CONCLUSION: The findings of this study suggest that acarbose can reduce serum levels of TG and TC. However, no significant effects were observed on LDL or HDL levels.


Assuntos
Dislipidemias , Lipídeos , Adulto , Humanos , Acarbose/farmacologia , Acarbose/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Triglicerídeos , Biomarcadores , Lipoproteínas HDL
11.
BMC Complement Med Ther ; 23(1): 370, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37864233

RESUMO

BACKGROUND: Obesity is a global health issue arising from the unhealthy accumulation of fat. Medicinal plants such as Alstonia boonei stem bark has been reported to possess body weight reducing effect in obese rats. Thus, this study sought to investigate the in vitro and in silico effects of fractions from Alstonia boonei stem bark on selected obesity-related digestive enzymes and adipogenesis in 3T3-L1 preadipocytes. METHOD: Two fractions were prepared from A. boonei: crude alkaloid fraction (CAF) and crude saponin fraction (CSF), and their phytochemical compounds were profiled using Liquid chromatography with tandem mass spectrometry (LCMS/MS). The fractions were assayed for inhibitory activity against lipase, α-amylase and α-glucosidase, likewise their antiadipogenic effect in 3T3-L1 adipocytes. The binding properties with the 3 enzymes were also assessed using in silico tools. RESULTS: Eleven alkaloids and six saponin phytochemical compounds were identified in the CAF and CSF using LCMS/MS. The CAF and CSF revealed good inhibitory activity against pancreatic lipase enzyme, but weak and good activity against amylase respectively while only CSF had inhibitory activity against α-glucosidase. Both fractions showed antiadipogenic effect in the clearance of adipocytes and reduction of lipid content in 3T3-L1 adipocytes. The LCMS/MS identified compounds (41) from both fractions demonstrated good binding properties with the 3 enzymes, with at least the top ten compounds having higher binding energies than the reference inhibitors (acarbose and orlistat). The best two docked compounds to the three enzymes were firmly anchored in the substrate binding pockets of the enzymes. In a similar binding pattern as the reference acarbose, Estradiol-17-phenylpropionate (-11.0 kcal/mol) and 3α-O-trans-Feruloyl-2 α -hydroxy-12-ursen-28-oic acid (-10.0 kcal/mol) interacted with Asp197 a catalytic nucleophile of pancreatic amylase. Estradiol-17-phenylpropionate (-10.8 kcal/mol) and 10-Hydroxyyohimbine (-10.4 kcal/mol) interacted with the catalytic triad (Ser152-Asp176-His263) of pancreatic lipase while Estradiol-17-phenylpropionate (-10.1 kcal/mol) and 10-Hydroxyyohimbine (-9.9 kcal/mol) interacted with Asp616 and Asp518 the acid/base and nucleophilic residues of modelled α-glucosidase. CONCLUSION: The antiobesity effect of A. boonei was displayed by both the alkaloid and saponin fractions of the plant via inhibition of pancreatic lipase and adipogenesis.


Assuntos
Alcaloides , Alstonia , Saponinas , Camundongos , Ratos , Animais , Adipogenia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Alstonia/metabolismo , Células 3T3-L1 , Acarbose/farmacologia , alfa-Glucosidases , Casca de Planta , Obesidade/metabolismo , Lipase/metabolismo , Alcaloides/farmacologia , Amilases/farmacologia , Saponinas/farmacologia
12.
Molecules ; 28(17)2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37687228

RESUMO

The inhibition of carbohydrate digestion by plant bioactive compounds is a potential dietary strategy to counteract type 2 diabetes. Indeed, inhibition of α-amylase, a key enzyme that carries out the bulk of starch digestion, has been demonstrated for a range of bioactive compounds including anthocyanins; however, sample pigmentation often interferes with measurements, affecting colorimetric assay outcomes. Therefore, the present study compared the performance of a direct chromogenic assay, using 2-chloro-4 nitrophenyl α-D-maltotrioside (CNPG3) as a substrate, with the commonly used 3,5-dinitrosalicylic acid (DNS) assay. The direct chromogenic assay demonstrated a 5-10-fold higher sensitivity to determine α-amylase inhibition in various samples, including acarbose as a reference, pure anthocyanins, and anthocyanin-rich samples. The IC50 values of acarbose presented as 37.6 µg/mL and 3.72 µg/mL for the DNS assay and the direct chromogenic assay, respectively, whereas purified anthocyanins from blackcurrant showed IC50 values of 227.4 µg/mL and 35.0 µg/mL. The direct chromogenic assay is easy to perform, fast, reproducible, and suitable for high-throughput screening of pigmented α-amylase inhibitors.


Assuntos
Diabetes Mellitus Tipo 2 , alfa-Amilases , Humanos , Acarbose/farmacologia , Antocianinas/farmacologia
13.
Bioorg Chem ; 141: 106846, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37713948

RESUMO

Herein, a novel series of 4,5-diphenyl-imidazol-α-aminophosphonate hybrids 4a-m was designed, synthesized, and evaluated as new anti-diabetic agents. These compounds were evaluated against two important target enzymes in the diabetes treatment: α-glucosidase and α-amylase. These new compounds were synthesized in three steps and characterized by different spectroscopic techniques. The in vitro evaluations demonstrated that all the synthesized compounds 4a-m were more potent that standard inhibitor acarbose against studied enzymes. Among these compound, the most potent compound against both studied enzymes was 3-bromo derivative 4l. The latter compound with IC50 = 5.96 nM was 18-times more potent than acarbose (IC50 = 106.63 nM) against α-glucosidase. Moreover, compound 4l with IC50 = 1.62 nM was 27-times more potent than acarbose (IC50 = 44.16 nM) against α-amylase. Molecular docking analysis revealed that this compound well accommodated in the binding site of α-glucosidase and α-amylase enzymes with notably more favorable binding energy as compared to acarbose.


Assuntos
Acarbose , Inibidores de Glicosídeo Hidrolases , Acarbose/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Hipoglicemiantes/química , alfa-Amilases/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular
14.
Sci Rep ; 13(1): 15672, 2023 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-37735489

RESUMO

α-Glucosidase inhibition is an approved treatment for type 2 diabetes mellitus (T2DM). In an attempt to develop novel anti-α-glucosidase agents, two series of substituted imidazo[1,2-c]quinazolines, namely 6a-c and 11a-o, were synthesized using a simple, straightforward synthetic routes. These compounds were thoroughly characterized by IR, 1H and 13C NMR spectroscopy, as well as mass spectrometry and elemental analysis. Subsequently, the inhibitory activities of these compounds were evaluated against Saccharomyces cerevisiae α-glucosidase. In present study, acarbose was utilized as a positive control. These imidazoquinazolines exhibited excellent to great inhibitory potencies with IC50 values ranging from 12.44 ± 0.38 µM to 308.33 ± 0.06 µM, which were several times more potent than standard drug with IC50 value of 750.0 ± 1.5 µM. Representatively, compound 11j showed remarkable anti-α-glucosidase potency with IC50 = 12.44 ± 0.38 µM, which was 60.3 times more potent than positive control acarbose. To explore the potential inhibition mechanism, further evaluations including kinetic analysis, circular dichroism, fluorescence spectroscopy, and thermodynamic profile were carried out for the most potent compound 11j. Moreover, molecular docking studies and in silico ADME prediction for all imidazoquinazolines 6a-c and 11a-o were performed to reveal their important binding interactions, as well as their physicochemical and drug-likeness properties, respectively.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores de Glicosídeo Hidrolases , Humanos , Inibidores de Glicosídeo Hidrolases/farmacologia , Acarbose/farmacologia , Quinazolinas/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cinética , Simulação de Acoplamento Molecular , Saccharomyces cerevisiae , alfa-Glucosidases
15.
Int J Biol Macromol ; 249: 126047, 2023 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-37517764

RESUMO

Inhibiting pancreatic α-amylase activity can decrease the release rate of glucose, thereby delaying postprandial blood glucose. This study aimed to investigate the physicochemical properties and porcine pancreatic α-amylase (PPA) inhibitory activities of five bacterial exopolysaccharides (EPSs). We also aimed to analyze the differences of their inhibitory activities, exploring the inhibition mechanism between EPSs and PPA. Five EPSs had a low molecular weight (55-66 kDa), which were mainly composed of mannose and glucose with total content exceeding 86 %. The IC50 values of five EPSs (0.162-0.431 mg/mL) were significantly lower than that of acarbose (0.763 mg/mL), indicating that the inhibitory effects of five EPSs on PPA were stronger than acarbose, especially the EPS from Bacillus subtilis STB22 (BS-EPS). Moreover, BS-EPS was a mixed-type inhibitor, whereas other EPSs were noncompetitive inhibitors of PPA. Five EPSs quenched the fluorophore of PPA by the mixed quenching or apparent static quenching. Interestingly, BS-EPS showed stronger binding affinity to PPA than other EPSs. It can be speculated that EPSs with low molecular weight, high carboxylic acid content, and α-glycosidic bond exhibited high PPA inhibitory activity. These results suggest that BS-EPS can effectively inhibit PPA activity and has potential applications in reducing postprandial hyperglycemia.


Assuntos
Acarbose , Hiperglicemia , Animais , Suínos , Acarbose/farmacologia , alfa-Amilases Pancreáticas , Glucose , Pâncreas/metabolismo , Polissacarídeos Bacterianos/farmacologia , Polissacarídeos Bacterianos/química
16.
J Cell Mol Med ; 27(15): 2249-2260, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37403218

RESUMO

In the present study, the identification of potential α-amylase inhibitors is explored as a potential strategy for treating type-2 diabetes mellitus. A computationally driven approach using molecular docking was employed to search for new α-amylase inhibitors. The interactions of potential drugs with the enzyme's active site were investigated and compared with the contacts established by acarbose (a reference drug for α-amylase inhibition) in the crystallographic structure 1B2Y. For this active site characterization, both molecular docking and molecular dynamics simulations were performed, and the residues involved in the α-amylase-acarbose complex were considered to analyse the potential drug's interaction with the enzyme. Two potential α-amylase inhibitors (AN-153I105594 and AN-153I104845) have been selected following this computational strategy. Both compounds established a large number of interactions with key binding site α-amylase amino acids and obtained a comparable docking score concerning the reference drug (acarbose). Aiming to further analyse candidates' properties, their ADME (absorption, distribution, metabolism, excretion) parameters, druglikeness, organ toxicity, toxicological endpoints and median lethal dose (LD50 ) were estimated. Overall estimations are promising for both candidates, and in silico toxicity predictions suggest that a low toxicity should be expected.


Assuntos
Acarbose , Diabetes Mellitus Tipo 2 , Humanos , Acarbose/farmacologia , Acarbose/química , Acarbose/uso terapêutico , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , Avaliação Pré-Clínica de Medicamentos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , alfa-Amilases
17.
Nat Metab ; 5(6): 955-967, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37365290

RESUMO

Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during normative ageing, also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh syndrome. Here we show that another drug that extends lifespan and delays normative ageing in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of inhibition of the mechanistic target of rapamycin. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short-chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression, while depletion of the endogenous microbiome in Ndufs4-/- mice appears to fully recapitulate the effects of acarbose on healthspan and lifespan in these animals. To our knowledge, this study provides the first evidence that alteration of the gut microbiome plays a significant role in severe mitochondrial disease and provides further support for the model that biological ageing and severe mitochondrial disorders share underlying common mechanisms.


Assuntos
Doença de Leigh , Doenças Mitocondriais , Camundongos , Animais , Doença de Leigh/tratamento farmacológico , Doença de Leigh/genética , Acarbose/farmacologia , Acarbose/uso terapêutico , Doenças Mitocondriais/tratamento farmacológico , Mitocôndrias/genética , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons
19.
Rejuvenation Res ; 26(4): 139-146, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37166369

RESUMO

Acarbose (ACA), a well-studied and effective inhibitor of α-amylase and α-glucosidase, is a postprandial-acting antidiabetic medicine. The membrane of the erythrocyte is an excellent tool for analyzing different physiological and biochemical activities since it experiences a range of metabolic alterations throughout aging. It is uncertain if ACA modulates erythrocyte membrane activities in an age-dependent manner. As a result, the current study was conducted to explore the influence of ACA on age-dependent deteriorated functions of transporters/exchangers, disrupted levels of various biomarkers such as lipid hydroperoxides (LHs), protein carbonyl (PCO), sialic acid (SA), total thiol (-SH), and erythrocyte membrane osmotic fragility. In addition to a concurrent increase in Na+/H+ exchanger activity and concentration of LH, PCO, and osmotic fragility, we also detected a considerable decrease in membrane-linked activities of Ca2+-ATPase (PMCA) and Na+/K+-ATPase (NKA), as well as concentrations of SA and -SH in old-aged rats. The aging-induced impairment of the activities of membrane-bound ATPases and the changed levels of redox biomarkers were shown to be effectively restored by ACA treatment.


Assuntos
Acarbose , Envelhecimento , Membrana Eritrocítica , Inibidores de Glicosídeo Hidrolases , ATPases Transportadoras de Cálcio da Membrana Plasmática , ATPase Trocadora de Sódio-Potássio , Acarbose/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Membrana Eritrocítica/química , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/enzimologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Peróxidos Lipídicos/análise , Ácidos Siálicos/análise , Carbonilação Proteica/efeitos dos fármacos , Compostos de Sulfidrila/análise , Fragilidade Osmótica/efeitos dos fármacos , Animais , Ratos , Masculino , Ratos Wistar , ATPases Transportadoras de Cálcio da Membrana Plasmática/análise , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , ATPase Trocadora de Sódio-Potássio/análise , ATPase Trocadora de Sódio-Potássio/metabolismo , Oxirredução/efeitos dos fármacos , Biomarcadores/análise , Biomarcadores/metabolismo
20.
Food Chem ; 420: 136102, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37060666

RESUMO

Tartary buckwheat has been shown to provide a good antihyperglycemic effect. However, it is unclear which active compounds play a key role in attenuating postprandial hyperglycemia. Presently, acetone extract from the hull of Tartary buckwheat had the best effect for α-glucosidase inhibition (IC50 = 0.02 mg/mL). Twelve potential α-glucosidase inhibitors from Tartary buckwheat were screened and identified by the combination of ultrafiltration and high-performance liquid chromatography coupled with mass spectrometry. Myricetin and quercetin exhibited the highest anti-α-glucosidase activity with IC50 values of 0.02 and 0.06 mg/mL, respectively. These inhibitors manifested different types of inhibition manners against α-glucosidase via direct interaction with the amino acid residues. The results of structure-activity relationships indicated that an increase in the number of -OH on the B-ring greatly strengthened α-glucosidase inhibitory activity, but glucoside and rutinoside replacement on the C-ring obviously weakened this influence. Furthermore, a synergistic effect was observed between inhibitors with different inhibition manners.


Assuntos
Fagopyrum , Inibidores de Glicosídeo Hidrolases , Inibidores de Glicosídeo Hidrolases/farmacologia , Acarbose/farmacologia , Acarbose/metabolismo , Fagopyrum/química , Hipoglicemiantes/química , alfa-Glucosidases/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...